Hexosaminidase-A, Tay–Sachs Disease and Brain .

Author

Prof. Hayk S. Arakelyan. Full Professor in Medicine,

Doctor of Medical Sciences, Ph.D , Grand Ph.D .

Senior Expert of Interactive Clinical Pharmacology , Drug Safety,

Treatment Tactics, General Medicine and Clinical Research.

“Natural forces within us are

the true healers of disease.”

“Hippocrates”

Introduction.

Tay-Sachs is caused by the absence of a vital enzyme called hexosaminidase-A

(Hex-A). Without Hex-A, a fatty substance, or lipid, called GM2 ganglioside
accumulates abnormally in cells, especially in the nerve cells of the brain. This
ongoing accumulation causes progressive damage to the cells. Tay–Sachs
disease is a genetic disorder that results in the destruction of nerve cells in
the brain and spinal cord. The most common type, known as infantile Tay–
Sachs disease, becomes apparent around three to six months o f age with the
baby losing the ability to turn over, sit, or crawl. The disease is named
after Waren Tay, who in 1881 first described a symptomatic red spot on
the retina of the eye; and Bernard Sachs, who described in 1887
the cellular changes and noted an increased rate of disease in Ashkenazi Jews.

Cause.

Tay–Sachs disease is caused by a genetic mutation in the HEXA gene

on chromosome 15. It is inherited from a person's parents in an autosomal
recessive manner. The mutation results in problems with an enzyme called beta-
hexosaminidase A which results in the buildup of the molecule GM2
ganglioside within cells, leading to toxicity.
Genetics.
Tay–Sachs results from mutations in the HEXA gene on chromosome 15, which
encodes the alpha-subunit of beta-N-acetylhexosaminidase A,
a lysosomal enzyme. By 2000, more than 100 different mutations had been
identified in the human HEXA gene. These mutations have included single base
insertions and deletions, splice phase mutations, missense mutations, and other
more complex patterns. Each of these mutations alters the gene's protein
product (i.e., the enzyme), sometimes severely inhibiting its function.

Diagnosis .
In patients with a clinical suspicion for Tay–Sachs disease, with any age of onset,
the initial testing involves an enzyme assay to measure the activity of
hexosaminidase in serum, fibroblasts, or leukocytes. Total hexosaminidase
enzyme activity is decreased in individuals with Tay-Sachs as is the
percentage of hexosaminidase A. After confirmation of decreased enzyme
activity in an individual, confirmation by molecular analysis can be pursued. All
patients with infantile onset Tay–Sachs disease have a "cherry red" macula in
the retina, easily observable by a physician using an ophthalmoscope.

Signs and Symptoms.

Tay–Sachs disease is typically first noticed in infants around 6 months old

displaying an abnormally strong response to sudden noises or other
stimuli, known as the "startle response". There may also be listlessness or
muscle stiffness (hypertonia). The disease is classified into several forms,
which are differentiated based on the onset age of neurological symptoms. -
-Infantile Tay–Sachs disease. Infants with Tay–Sachs disease appear to
develop normally for the first six months after birth. Then, as neurons become
distended with gangliosides, a relentless deterioration of mental and physical
abilities begins. The child may become blind, deaf, unable
to swallow, atrophied, and paralytic. Death usually occurs before the age of
four.[6]

-Juvenile Tay–Sachs disease. Juvenile Tay–Sachs disease is rarer than other

forms of Tay–Sachs, and usually is initially seen in children between two and
ten years old. People with Tay–Sachs disease develop cognitive and motor
skilldeterioration, dysarthria, dysphagia, ataxia, and spasticity.[8] Death usually
occurs between the age of five to fifteen years.

-Adult/Late-Onset Tay–Sachs disease. A rare form of this disease, known as

Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms
during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs
 disease is usually not fatal as the effects can stop progressing. It is frequently
misdiagnosed. It is characterized by unsteadiness of gait and progressive
neurological deterioration. Symptoms of late-onset Tay–Sachs – which
typically begin to be seen in adolescence or early adulthood –
include speech and swallowing difficulties, unsteadiness of gait, spasticity,
cognitive decline, and psychiatric illness, particularly a schizophrenia-
like psychosis.[10] People with late-onset Tay–Sachs may become full-
time wheelchair users in adulthood.
Until the 1970s and 1980s, when the disease's molecular genetics became known,
the juvenile and adult forms of the disease were not always recognized as variants
of Tay–Sachs disease. Post-infantile Tay–Sachs was often misdiagnosed as another
neurological disorder, such as Friedreich's ataxia.

Prevention.
Three main approaches have been used to prevent or reduce the incidence of
Tay–Sachs:

-Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic

testing can determine whether the fetus has inherited a defective gene copy
from both parents.[26] Chorionic villus sampling (CVS), the most common form
of prenatal diagnosis, can be performed between 10 and 14 weeks
of gestation. Amniocentesis is usually performed at 15–18 weeks. These
procedures have risks of miscarriage of 1% or less.[27][28]

-Preimplantation genetic diagnosis. By retrieving the mother's eggs for in

vitro fertilization, it is possible to test the embryo for the disorder prior to
implantation. Healthy embryos are then selected and transferred into the
mother's womb, while unhealthy embryos are discarded. In addition to Tay–
Sachs disease, preimplantation genetic diagnosis has been used to
prevent cystic fibrosis and sickle cell anemia among other genetic disorders.[29]

-Mate selection. In Orthodox Jewish circles, the organization Dor

Yeshorim carries out an anonymous screening program so that carrier couples
for Tay–Sachs and other genetic disorders can avoid marriage.

If you have any questions concerning “ Hexosaminidase-A, Tay–Sachs

Disease and Brain .”, interactive clinical pharmacology , or any other
questions, please inform me .

Prof. Hayk S. Arakelyan